OVERVIEW ? ABSTRACT Plasma cells (PC) constitute the effector arm of the humoral immune system and are responsible for serum and tissue antibodies. PC combine properties of resting, long-lived memory cells and of effector cells endowed with constitutive antibody production thereby suggesting their regulation by unique molecular programs. PC protect against new pathogens and maintain long-lasting serological memory against historical pathogens. Accordingly, PC are at the core of protective responses in infection, vaccination and anti-tumor immunity. However, PC also induce antibody-mediated diseases including autoimmunity, allergy and transplant rejection. Indeed, the activation of PC differentiation in response to self-antigens, alloantigens or allergens carries a major risk by creating undesirable pro-inflammatory responses. This situation is all the more detrimental when it involves a unique type of PC that may survive for the lifetime of the patient (long lived plasma cells; LLPC). Accordingly, understanding programs that govern the differentiation and survival of different types of PC and how these programs are subverted in human diseases is of the utmost importance to enhance protective PC responses and regulate pathogenic responses. Unfortunately, PC are severely understudied as a cell type and as mediators of disease. Our ability to address these questions has been hampered by knowledge gaps and experimental barriers including lack of specific markers for LLPC. We seek to remedy these deficiencies by using the knowledge we have gained in the understanding of the phenotypic and functional heterogeneity of human PC (Projects 2-4), and through the use of animal models of PC differentiation and participation in disease under well-defined T cell-dependent and ?independent conditions (Projects 1-2). This PPG will ask fundamental questions through complementary and synergistic projects that will generate high-density datasets of transcriptional and epigenetic programs induced under different experimental conditions. These questions include: 1) Epigenetic regulation of PC differentiation and survival in mice (Projects 1-2) and humans (Projects 2, 3, 4); 2) Transcriptional and epigenetic modulation of functionally distinct PC populations by cytokines and cytokine-induced transcriptional factors (Project 2); 3) Mechanisms of human LLPC survival through adaptation to the bone marrow microenvironment (Project 3); and 4) Mechanisms of generation and survival of pathogenic autoreactive LLPC in human SLE (Project 4). These questions will be addressed through the interaction of scientists with significant contributions in relevant areas and a strong track record of collaborations. All molecular studies will be performed by an Epigenomics, Sequencing, and Bioinformatics Core to ensure data quality, reproducibility and sharing. An Administrative Core will provide leadership, administrative, regulatory and financial infrastructure. The knowledge generated will be invaluable to develop more effective, selective and safe PC therapies. It will also identify biomarkers for segmentation, personalized treatment and monitoring of multiple antibody-mediated diseases.